exploring the activity of rad001 in vestibular schwannomas and meningiomas

Conditions: Neurofibromatosis Type 2; Vestibular Schwannomas; Meningiomas

Summary: the primary objective is to estimate the proportions of vestibular schwannomas (vs) and meningiomas after 10 days of exposure to the study drug rad001 at a dose of 10 mg daily, as determined by immunohistochemistry. this is a "phase 0" pk (pharmacokinetic) and pd (pharmacodynamic) study of rad001 in patients with neurofibromatosis type 2-related and sporadic vs and meningiomas. enrolled patients will take rad001 prior to a scheduled vs or meningioma surgery, and blood and tissue samples will be obtained for further analysis.


Eligibility criteria:
inclusion criteria: * patients must satisfy all of the following eligibility criteria: * karnofsky performance status (kps) ≥ 60% * absolute neutrophil count ≥ 1,000/mm³ (unsupported) * platelet count ≥ 100,000/mm³ (unsupported) * hemoglobin ≥ 8 g/dl (transfusion support allowed) * creatinine ≤ 1.5 times upper limit of normal (uln\*) or corrected glomerular filtration rate ≥ 70 ml/min * total bilirubin ≤ 1.5 times uln\* * alt ≤ 2.5 times uln\* * serum albumin ≥ 2 g/dl * inr \< 1.3 (or \< 3 on anticoagulants) * patients taking a cholesterol-lowering agent must be on a single medication and on a stable dose for at least 4 weeks * fasting serum cholesterol ≤ 300 mg/dl or ≤ 7.75 mmol/l and fasting triglycerides ≤ 2.5 times uln\*. * fully recovered from acute toxic effects of any prior chemotherapy, biological modifiers or radiotherapy * any neurologic deficits must be stable for ≥ 1 week * patients with the potential for pregnancy or impregnating their partner must agree to follow acceptable birth control methods to avoid conception. women of childbearing potential must have a negative pregnancy test. the anti-proliferative activity of this experimental drug may be harmful to the developing fetus. * able to provide written informed consent exclusion criteria: * patients with any of the following are ineligible for this research study: * patients with vs or meningiomas deemed very high surgical risk for stroke and/or other complications by the attending surgeon, such as meningiomas with major vascular or dural sinus infiltration. * patients with serious concurrent infection or medical illness, which would jeopardize the ability of the patient to receive the treatment outlined in this protocol with reasonable safety. * symptomatic congestive heart failure or unstable angina pectoris. * uncontrolled diabetes, as defined by fasting serum glucose \>1.5 times uln\*. * current active hepatic or biliary disease such as cirrhosis, chronic active hepatitis, or chronic persistent hepatitis (with exception of patients with gilbert's syndrome and asymptomatic gallstones). * history of hepatitis b or c. note: a detailed assessment of hepatitis b/c medical history and risk factors must be done at screening for all patients. hbv serology, dna and/or hcv rna pcr testing are required at screening for all patients with a positive medical history based on risk factors and/or confirmation of prior hbv/hcv infection. if no positive medical history for risk factors, serology is not required. * seropositivity or dna/rna positivity for hepatitis b or c, with the exception of patients who have received prior hepatitis b vaccination and are anti-hbs positive only. * known hiv seropositivity * neurologic deficits that are rapidly progressing: all neurologic signs and symptoms must have been stable for a week prior to first dose * patients who are pregnant or breast-feeding. the anti-proliferative activity of this experimental drug may be harmful to the developing fetus or nursing infant. * anti-tumor therapy (i.e. chemotherapeutics or investigational agents or immunotherapy) within 4 weeks prior to enrollment * radiation therapy to a study target lesion within 6 months * prior therapy with mtor inhibitors, including sirolimus, temsirolimus, deforolimus within 6 months prior to enrollment * known hypersensitivity to rad001 or other rapamycins (sirolimus, temsirolimus, deforolimus) * patients with a concurrent malignancy * patients treatment with systemic steroids or another immunosuppressive agent. patients with endocrine deficiencies are allowed to receive physiologic or stress doses of steroids if necessary. * patients cannot receive cyp3a4 inhibiting drugs including antibiotics (clarithromycin, erythromycin, troleandomycin), anti-hiv agents (delaviridine, nelfinavir, amprenavir, ritonavir, indinavir, saquinavir, lopinavir), antifungals (itraconazole, ketoconazole, fluconazole at doses \> 200 mg/day, voriconazole), antidepressants (nefazodone, fluovoxamine), calcium channel blockers (verapamil, diltiazem) oramiodarone * patients should avoid cyp3a4 inhibiting foods including grapefruit and seville orange juice. * patients cannot receive cyp3a4 inducing anticonvulsants including carbamazepine, felbamate, phenobarbital, phenytoin, primidone and oxcarbazepine, or other cyp3a4 inducers such as st. john's wort * patients who previously received cyp3a4 inducers or inhibitors must have discontinued these medications within at least 1 week prior to study entry and can re-start them 1 week post-operatively (or earlier if determined to be of clinical benefit, as determined by the treating physician). * of institutional norms